Mitochondrial Dysfunction - Case Study Example

Running Head: Role of mitochondrial dysfunction in Alzheimer’s disease [Name] [Professor Name] [Course] [Date] Table of Contents Table of Contents 1 Introduction 3 PART I 4 Description of Alzheimer disease process 4 PART II 6 Annotated Bibliography 6 Article 1 6 Article 2 8 PART III 9 Evaluation of the text’s Contribution 9 Conclusion 10 Reference 12 Does mitochondrial dysfunction play a role in Alzheimer’s disease? Introduction Mitochondrial dysfunction has been associated with certain neurodegenerative disorders such as Alzheimer’s disease. There is growing evidence suggesting that mitochondria play a critical role in the neurodegenerative disease. More specifically, mitochondrial dysfunction contributes to reduced production of ATP, impaired calcium buffering and augmented generation of reactive oxygen species (Moreira, 2010). The brain is typically susceptive to oxidative damage and mitochondrial DNA (mtDNA) mutations. The genes concerned with the maintenance of mtDNA are linked with the variable spectrum of mitochondrial disorders that affect the brain (Nowotny, Kwon and Goate, 1998). This paper argues that mitochondrial dysfunction plays a role in Alzheimer disease. Within this broad perspective, it hopes to provide a critical understanding of the correlation between mitochondrial dysfunction to Alzheimer disease. The basis of this argument is that mitochondrial function is important for neuronal survival and differentiation. The purpose of this paper is therefore to establish the role that mitochondrial dysfunction plays in Alzheimer disease. The thesis statement is that mitochondrial dysfunction does indeed play a significant role in Alzheimer disease. By adopting on this presumption, this paper adopts the mitochondrial cascade hypothesis that seeks to unify the explanation of histological, biochemical and clinical features of Alzheimer’s disease. This paper provides an insight into the association of mitochondrial DNA (mtDNA) with the susceptibility to Alzheimer’s disease (Swerdlow, 2007). PART I Description of Alzheimer disease process Alzheimer disease is a form of dementia and a progressive disease that is generally associated with ageing. It affects the brain and subsequently affecting thinking, memory and behaviour. The term dementia refers to a group of symptoms such as mood changes, memory, reasoning problem and communication problem (Swerdlow, 2007). The causes for the majority Alzheimer’s disease cases are in actual fact still unknown, except for around 5 percent of apposite cases, where a combination of environmental and genetic cases have been identified. A major risk factor is age, with the prevalence estimated to double each five years from the ages of 65 to 85 years. Additional risk factors include Down Syndrome, inheritance of the e4 allele of the ApoE as well as having a relative with a first-degree Alzheimer’s disease (Nowotny, Kwon and Goate, 2001). A number of theories have attempted to explain the pathogenesis of Alzheimer disease. Cholinergic hypothesis suggests that the disease is caused by the progressive decreases in the synthesis of neurotransmitter acetylcholine. Amyloid hypothesis proposes that deposits of beta-amyloid (Aβ) are the basic causes of the disease. Proponents of this hypothesis postulate that the location of the gene for amyloid precursor protein (APP) on chromosome 21, along with individuals with Down syndrome (trisomy 21), who have an extra gene copy may develop Alzheimer disease (Armstrong, 2010; Hasegawa, Mikoda, Kitazawa and LaFerla, 2010). Additionally, the particular isoform of apolipoprotein (APOE4), leads to excessive amyloid accumulation in the brain causing the disease. Tau hypothesis fronts the idea that protein abnormalities can trigger the disease cascades. According to this hypothesis, hyperphosphorylated tau starts pairing with other tau threads ultimately forming neurofibrillary tangles within the nerve cell bodies. As a result, microtubules disintegrate that disintegrate the neuron’s transport system (Khan, 2008; Calkins et al, 2011). This causes malfunction in neuron biochemical communication subsequently causing death of the cells. This causes Alzheimer disease. The mitochondrial cascade hypothesis assumes that similar physilogica mechanisms trigger brain ageing and Alzheimer disease. It hypothesizes that Alzheimer disease brain mitochondrial dysfunction encourages cell cycle re-entry, tau phosphorylation and amyloidosis (Swerdlow, 2007). Diagnosis of Alzheimer disease can be effectively done through the examination of brain for characteristics of pathology. In any case, effective diagnosis happens through the use of neuropsychological testing, standard dementia screening tools, progressive worsening of memory between the ages of 40 and 90 years. Generally, it is diagnosed at the age of 65 years, when it is classified under late-onset Alzheimer disease. Those that develop the symptoms before 65 years (early onset Alzheimer disease) have an inherited form of the disease. The early symptoms include; language problems, memory loss, loss of social skills, difficulty in performing tasks, changes in personality. Late symptoms include change in sleep patterns, poor judgment, difficulty in reading, hallucinations and lack of comprehension of language and recognition of family members (Swerdlow, 2007). Currently, there is no cure for Alzheimer disease. However, there are several drug treatments available for alleviating the symptoms momentarily or decelerating their progression. Since individuals with the disease have been proved to have deficiency of chemical acetylcholine in the brain, the recommended drugs are intended to maintain the existing supply of acetylcholine in the brain. Typical drugs include Exelon, Aricept and Reminyl (Alzheimer's Society, 2013). PART II Annotated Bibliography Article 1 Castellani, R., Hirai, K., Aliev, G., Drew, K., Nunomura, A., Takeda, A., Cash, A., Obrenovicj, M., Perry, G., Smith, M. (2002). "Role of Mitochondrial Dysfunction in Alzheimer’s Disease." Journal of Neuroscience Research, 70(1):357–360 The article examines how abnormalities in mitochondrial function are related to the spectrum of pathological changes exhibited by persons with Alzheimer disease. The article reviews the causes and impacts of mitochondrial disturbances in the disease and how the information may affect the therapeutic approaches to the disease (Castellani et al, 2002). The author’s fundamental thesis statement is that abnormalities in the mitochondrial function are correlated with the scale of pathological changes exhibited by Alzheimer’s disease. Based on its objective of examining how abnormalities in mitochondrial function are related to the spectrum of pathological changes exhibited by persons with Alzheimer disease, it is critical to argue that the article is targeted for researchers in the academia, medical practitioners, research scientists looking to further researches in the field, nurses and the general public interest looking for information on pathogenesis of Alzheimer disease (Castellani et al, 2002). The article concludes that mitochondrial defects play a significant role in triggering nueogenerative disease and Alzheimer’s disease in particular. It shows that the neurons in Alzhemimer disease patients accumulate mitochondrial debris in their perikaryon that result from oxidative damage to mitochondrial proteins and mitochondrial DNA, which is correlated with defective microtubule metabolism (Castellani et al, 2002). The study found that the same neurons that showed increased oxidative damage in Alzheimer disease caused significant increase in mitochondrial DNA and cytocochrome oxidase. Consequently, the abnormal mitochondrial turnover that is indicated by the increasing mitochondrial protein accumulation and perikaryal mtDNA despite decreased number of mitochondria may be caused by deficient mitochondrial transport (Calkins et al, 2011). Deficient mitochondrial transport may in turn initiate pathological cascade of events in the parikaryal mitochondria this affects energy metabolism leading to metabolic stress in the AD brain (Castellani et al, 2002). The primary reason for choosing the article is because it offers insight into a laboratory evidence of the role of mitochondria in Alzheimer disease. In particular, it evidences that neorons in AD brains accumulate mitochondrial fragments in their perikaryon resulting from oxidative damage to mtDNA and mitochondria proteins. This article is therefore relevant to the thesis statement of this paper. Article 2 Du, H., Guo, L., Yan, S., Sosunov, A., McKhann, G. & Yan, S. (2010). "Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model." PNAS, 107(43):18607-18675 The article discusses how mitochondrial dysfunction and synaptic damage include some of the early features of Alzheimer disease. It further demonstrates the abnormalities of mitochondrial function as including decreased mitochondrial respiration and hypometabolism that happen in the Alzheimer disease brain. It also examines how Amyloid β (Aβ), an element that accumulates in the brain is an essential pathogenic peptide that directly affects mitochondrial function causing oxidative stress in the brain, resulting to Alzheimer disease (Du et al, 2010). The main argument promote by the text is that mitochondrial dysfunction and synaptic damage include some of the early features of Alzheimer disease. The articles is targeted for researchers in the academia, medical practitioners, research scientists looking to further researches in the field, nurses and the general public interest looking for information on pathogenesis of Alzheimer disease (Du et al, 2010). The article concludes that progressive accumulation of Amyloid β (Aβ), in synaptic mitochondria causes mitochondrial function and oxidative stress. These highlight the significance of synaptic mitochondria in regulating the synaptic strength and the effects of their disruption on the pathogenesis of Alzheimer disease (Du et al, 2010). The text was selected since it offers an insight into the role of mitochondria in Alzheimer disease. PART III Evaluation of the text’s Contribution Although on different accounts, both articles offer an insight into the role that mitochondria dysfunction plays in Alzheimer disease. Indeed, this reflects on the research question: Does mitochondrial dysfunction play a role in Alzheimer’s disease? The first article demonstrates that mitochondrial defects play a significant role in triggering nueogenerative disease and Alzheimer’s disease in particular. It further evidences that the neurons in Alzheimer disease patients accumulate mitochondrial debris in their perikaryon that result from oxidative damage to mitochondrial proteins and mitochondrial DNA, which is correlated with defective microtubule metabolism. Based on these facts, it is critical to observe that the article seeks to demonstrate how mitochondria dysfunctions contribute to the prevalence of the disease. For instance, it elucidates how degradation of mitochondria happens in Alzheimer disease leaving lysosomal detritus that contains non-functioning mitochondrial proteins. The article further demonstrates the role of deficient mitochondrial transport and how it has the potential to initiate pathological cascade of events in the parikaryal mitochondria thus affecting energy metabolism leading to metabolic stress in the AD brain. These demonstrate the role of mitochondrial dysfunction in Alzheimer disease. The knowledge promoted by the article can as a result be used to inform my ongoing research, as the role of mitochondrial defects in triggering nueogenerative disease and Alzheimer’s disease can be derived to explain the role that mitochondria dysfunctions plays in Alzheimer disease. The second article contributes to the knowledge that mitochondrial dysfunction and synaptic damage include some of the early features of Alzheimer disease. The role of mitochondrial dysfunction is subsequently discussed and how they contribute to the prevalence of the Alzheimer disease (Du et al, 2010). In essence, this is relevant as it attempts to answer the research question. It can therefore be analyzed that show the role of mitochondrial dysfunction, the abnormalities of mitochondrial function such as mitochondrial respiration and hypometabolism are examined. Since these happen in the brain, they cause some level of dementia on the patient. To further show the role of mitochondrial dysfunction, the article evidences how Amyloid β (Aβ) directly affects mitochondrial function causing oxidative stress in the brain, resulting to Alzheimer disease. The knowledge promoted by the article can as a result be used to inform my ongoing research. This is because the abnormalities of mitochondrial function such as mitochondrial respiration and hypometabolism that cause oxidative stress in the brain resulting to demential can be derived by the research to explain the role that mitochondria dysfunctions plays in Alzheimer disease (Du et al, 2010). Conclusion It can be concluded that mitochondrial dysfunction does indeed play a critical role in Alzheimer disease. The basis of this argument is that mitochondrial function is important for neuronal survival and differentiation. A critical understanding of the correlation between mitochondrial dysfunction to Alzheimer disease is evidenced through literature review of relevant sources. By adopting on these presumptions, this paper adopts the mitochondrial cascade hypothesis that seeks to unify the explanation of histological, biochemical and clinical features of Alzheimer’s disease. It hypothesizes that Alzheimer disease brain mitochondrial dysfunction encourages cell cycle re-entry, tau phosphorylation and amyloidosis. Two articles are selected that promote the mitochondrial cascade hypothesis. The first article is able to establish that mitochondrial defects play a significant role in triggering nueogenerative disease and Alzheimer’s disease in particular. It further shows that the neurons in Alzheimer disease patients accumulate mitochondrial debris in their perikaryon that result from oxidative damage to mitochondrial proteins and mitochondrial DNA, which is correlated with defective microtubule metabolism (Castellani et al, 2002). The second article is able to establish the role of mitochondrial dysfunction in Alzheimer disease by demonstrating how progressive accumulation of Amyloid β (Aβ) in synaptic mitochondria causes mitochondrial function and oxidative stress. These highlight the significance of synaptic mitochondria in regulating the synaptic strength and the effects of their disruption on the pathogenesis of Alzheimer disease. In summary therefore, it can be established that mitochondrial dysfunction does indeed play a role in Alzheimer’s disease. Reference Alzheimer's Society (2013). What is Alzheimer's disease?. Retrieved http://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=100 Armstrong, R. (2010). "The Pathogenesis of Alzheimer's Disease: A Reevaluation of the “Amyloid Cascade Hypothesis." International Journal of Alzheimer's Disease. Retrieved from Hindawi website http://www.hindawi.com/journals/ijad/2011/630865/ Calkins, M., Manczak, M., Mao, P., Shirendeb, U. & Reddy, H. (2011). "Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease." Hum. Mol. Genet, 20(23): 4515-4529. Castellani, R., Hirai, K., Aliev, G., Drew, K., Nunomura, A., Takeda, A., Cash, A., Obrenovicj, M., Perry, G., Smith, M. (2002). "Role of Mitochondrial Dysfunction in Alzheimer’s Disease." Journal of Neuroscience Research 70(1):357–360 Du, H., Guo, L., Yan, S., Sosunov, A., McKhann, G. & Yan, S. (2010). "Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model." PNAS, 107(43):18607-18675 Garcia-Escudero, V. Martin-Meastro, P., Perry, G. & Avila, J. (2013). "Deconstructing Mitochondrial Dysfunction in Alzheimer Disease." Oxidative Medicine and Cellular Longevity. Retrieved http://www.hindawi.com/journals/oximed/2013/162152/ Hasegawa, T., Mikoda, N., Kitazawa, M. & LaFerla, F. (2010). Treatment of Alzheimer's Disease with Anti-Homocysteic Acid Antibody in 3xTg-AD Male Mice. Retrieved http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0008593 Khan, A. (2008). "The amyloid hypothesis and potential treatments for Alzheimer's disease." The Journal of Quality Research in Dementia. Retrieved from Alzheimer's Society website http://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=383&pageNumber=6 Moreira, P. (2010). "Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease." European Neurological Review, 5(1):17-21 Nowotny, P., Kwon, J. & Goate, A. (1998). Alzheimer Disease. Saint Louis, Missouri: Washington University School of Medicine. Retrieved http://web.udl.es/usuaris/e4650869/docencia/segoncicle/genclin98/malalties/AlzheimerDisease.pdf Swerdlow, R. (2007) "Pathogenesis of Alzheimer’s disease." Clinical Intervention Aging, 2(3):347-459 Read More